Asymmetric synthesis of furo(3,4-c) pyridine derivatives

ABSTRACT

The invention relates to a method for the preparation of a non-racemic furo [3,4-c] pyridine derivatives of the formula I ##STR1## wherein R 1 , R 2  and R 3  stand for various substitutents, comprising adding a concentrated strong acid to a solution of a non-racemic compound of the formula II ##STR2## in an amount sufficient to catalyze a deprotection/cyclodehydration. These compounds are known antihypertensives.

The invention relates to a method for the preparation of non-racemicfuro [3, 4-c] pyridine derivatives.

In this Specification the term "non-racemic" is used to indicate asingle enantiomer or an enantiomer mixture in which one enantiomerpredominates.

It is now generally recognized that two enantiomers of a drug molecule,when introduced into a biological environment, behave as if they weredifferent chemical entities. These variations can be demonstrated asdifferences in:

1. protein binding,

2. metabolism,

3. pharmacokinetics,

4. tissue distribution,

5. receptor binding, and

6. enzyme inhibition;

and are caused by a difference in stereoconfiguration. The twoenantiomers are generally labelled as R or S or (-) or (+) todistinguish them.

Thus, in vivo, any racemic mixture is constantly subjected tostereodifferentiation by encountering chiral surroundings either insolution or when bound to solid phase structures (cell receptors, etc).As a result of this stereodifferentiation, enantiomers may not onlydiffer in therapeutic activity, but may behave antagonistically.

Consequently, it is becoming increasingly necessary for regulatoryapproval to provide toxicity, pharmacology, disposition and activitydata for each individual isomer as well as the drug racemate (i.e., a1:1 mixture of stereoisomers). This necessitates that methods beavailable for the generation of the optically pure drug enantiomers.Generally, three strategies can be employed to prepare pure isomericproducts:

1. preparation of a racemate of the desired compound and separation ofthe racemate into its enantiomers;

2. preparation of a racemate of the desired compound, conversion of theracemate into a racemic derivative, separation of the racemic derivativeinto its enantiomers, and reconversion of each enantiomer separatelyinto an enantiomer of the desired compound; and

3. asymmetric synthesis of individual enantiomers of the desiredcompound.

In typical organic synthesis, enantiomeric products are obtained withoutcontrol over the ratio of one type of stereoisomer to the other andstatistically these different enantiomers are obtained in a proportionof 1:1 to form a racemic mixture.

The invention is most particularly concerned with the conversion of anon-racemic compound of the general formula II ##STR3## wherein

R₁ represents a straight chain saturated or unsaturated hydrocarbongroup having from 1 to 5 carbon atoms, a heterocyclic group having up to6 ring atoms, a carbomonocyclic group, a phenyl group, a phenylalkylgroup or a phenylalkenyl group, each of said groups being optionallysubstituted by one or more halogen atoms, trifluoromethyl groups, alkylgroups having from 1 to 5 carbon atoms, alkoxy groups having from 1 to 5carbon atoms, alkylthio groups having from 1 to 5 carbon atoms,dialkylamine groups in which each of the two alkyl groups has from 1 to5 carbon atoms, dialkylaminoalkoxy groups in which each of the two alkylgroups and the alkoxy group has from 1 to 5 carbon atoms or an α- orβ-alkoxy-N-pyrrolidinyl group in which the alkoxy group has from 1 to 5carbon atoms;

R₂ represents a hydrogen or halogen atom; and

R₃ represents a straight chain or branched chain alkyl or alkenyl grouphaving up to 6 carbon atoms, optionally substituted by a hydroxy, cyano,amino or substituted amino group or by an alkyl or alkenyl group havingup to 4 carbon atoms

to the corresponding non-racemic furo [3,4-c] pyridine derivative of thegeneral formula I ##STR4## wherein R₁, R₂ and R₃ are as above defined.

A route is known for such a conversion, but is laborious, involving fivesteps as shown in the following reaction scheme: ##STR5##

The hydroxy group must first be protected. The acetonide blocking groupcan then be removed, and the resulting 4-hydroxymethyl group is thentosylated to provide for easier SN2 displacement subsequently. Theacetoxy protecting group is then removed, and a base catalysedcyclisation provides the desired compound.

The invention provides a method for conversion of a non-racemic compoundof the general formula II as herein defined to the correspondingnon-racemic furo [3,4-c] pyridine derivative of the general formula I asherein defined, the method comprising adding a concentrated strong acidto a solution of the compound II in an amount sufficient to catalyse adeprotection/cyclodehydration reaction. There is thus achieved in asingle step that which hitherto necessitated five steps.

Preferably the non-racemic compound II is dissolved in a solvent whichforms an azeotrope with water. From a variety of such solvents, theremay be mentioned benzene, toluene, ethyl acetate and chloroform.

The concentrated strong acid may be hydrochloric acid, sulphuric acid,perchloric acid or trifluoroacetic acid.

In a preferred embodiment, the starting material II is initiallypurified by alcohol or ethyl acetate crystallization before beingdissolved in the solvent. When the starting material of the generalformula II is optically enriched, i.e., 80/20, ethyl acetatecrystallization may provide a product that is typically greater than 95%optically pure.

The non-racemic furo [3,4-c] pyridine derivative may be recovered bydecanting the excess solution, including the unreacted compound of thegeneral formula II, from a residue produced by the cyclodehydrationreaction, dissolving the residue in alcohol to produce a mixture,determining what part of the alcohol mixture is a compound of thegeneral formula I, and isolating the same from the alcohol mixture.

The non-racemic compound II which is the starting material for themethod of the invention may be obtained from the corresponding racemiccompound by oxidation to a ketone of the general formula III ##STR6##wherein R₁, R₂ and R₃ are as defined hereinabove, followed bystereospecific reduction of the ketone. In detail, this method maycomprise:

(a) dissolving the racemic form of the compound of the general formulaII in an organic solvent to form a solution;

(b) adding dropwise an oxidizing agent to said solution in a sufficientamount to completely react with all the compound racemates of thegeneral formula II;

(c) quenching the excess oxidizing agent with an alcohol;

(d) cooling the liquid to produce a solid compound precipitate;

(e) dissolving said solid crystals in tetrahydrofuran to form a mixture;

(f) adding to said mixture a chiral reducing agent to reduce said solidcompound to the desired non-racemic compound of the general formula IIand

(g) isolating the non-racemic compound of the general formula II anddissolving it in a solvent.

The organic solvent may be acetone. A suitable oxidizing agent is JonesReagent (CrO₃ H₂ /H₂ SO₄ /H₂ O). The alcohol used in quenching issuitably isopropanol.

The initial stereocontrolled step of adding a hydride from a chiralmetal hydride or borohydride reagents to acyclic ketones has been widelyused for the preparation of optically active secondary alcohols, see forexample, Brown, H. C., et al., J. Org. Chem, 52: 5406-12 (1987).

The chiral reducing agent may be N,B-Enantride™ (Aldrich Chemical Co )or MDBH₂ (Expansia, European patent No. 0 061 408) in tetrahydrofuran(THF). Such reducing agents are produced by chiral modifications ofcomplex metal hydrides as well as borohydrides (Brown, H. C., et al., J.Org. Chem., 52: 5406-12 (1987).

N,B-Enantride™ is lithium hydrido (9-BBN-nopolbenzyl ether adduct), in a0.5 m solution in THF. The following reagents are all suitable for usein the present invention: B-Ipc-9-BBN (Alpine borane, Aldrich),N,B-Entrane (Aldrich), Ipc₂ BCl (Aldrich), BM₃ -ANDPB (2:1) (see S.Itsuno, J. Chem. Soc., Chem. Comm.1981, 315), (R,R)-2,5-dimethylborolane(see S. Masamune, J. Am Chem. Soc. 1986, 108, 7402), N,B-Enantride(Aldrich), LiBH₄ -DBC-t- BuOH (see K. Soal, J. Chem. Soc., Chem. Com.1984, 413), NaBH₄ -IBA-DIPGF (see S. Itsuno, J. Chem. Soc., PerkinTrans. 1, 1981, 900), K-Glucoride (see H. C. Brown, J. Org. Chem. 1986,51, 1934), LiAlH₄ -Darvon Alc (see H. Mosher, J. Am. Chem. Soc.,1972,94, 9254) LiAlH₄ -MEP-ArOH (see J. P. Vigneron, Tetrahedron 1976, 32,939), LiAlH₄ -Diamine (see M. Asami, Heterocycles, 1979, 12, 499),LiAlH₄ -Aminobutanol (see T. Sato, Tet. Letters 1982, 23, 4111), Binal H(See R. Noyori, J. Am. Chem. Soc. 1979, 101, 3129), LiAlH₄ -DBP-EtOH(see K. Yamamoto, J. Chem. Soc., Chem. Comm. 1984, 1490),LiAlH₄ -MEP-NEA(see K. J. Koga, J. Chem. Soc., Chem. Comm.1980,1026), LiAlH₄ -MEP-EAP(see S. Terashima, Chem. Letters 1984, 239), TBADH (Thermoanaerobiumbrockii alcohol dehydrogenase, Sigma Chem.Co.)

The non-racemic compound II may alternatively be obtained from theketone III by dissolving it in a vigorously stirred fermenting slurry ofyeast, water and a carbohydrate;

(b) adding additional carbohydrate and yeast to provide continuedvigorous fermentation to form the desired chiral compound of the generalformula II;

(c) continuing said fermentation until formation of the compound of thegeneral formula II ceases and

(d) isolating the compound of the general formula II.

The following Examples describe the preparation of the ketone III: R₁=4-chlorophenyl, R₂ =H, R₃ =CH₃ from the corresponding racemic alcoholII (Example 1), the preparation of the corresponding non-racemic alcoholII from the ketone III (Example 2), and the preparation of thecorresponding non-racemic furo [3,4-c] pyridine derivative I: R₁=4-chlorophenyl, R₂ =H, R₃ =CH₃ from the non-racemic alcohol II by themethod of the invention.

EXAMPLE 1 Synthesis of ketone III by oxidation of racemic2,2,8-trimethyl-5-(4-chloro-α-hydroxybenzyl)-pyrido-[4,3-e]-1,3-Dioxane

2.16 g (6,7 mmoles) of racemic 2,2,8-trimethyl-5-(4-chloro-α-hydroxybenzyl)-pyrido- [4,3-e]-1,3-dioxane were poured into anErlenmeyer flask and dissolved in 150 ml acetone. Jones reagent (CrO₃/H₂ SO₄ /H₂ O) was added dropwise to the stirred solution until thestarting material was completely used up as determined by TLC (thinlayer chromatography). Excess oxidizing agent was quenched inisopropanol. The reaction mixture was poured into iced water and thesolid that formed was removed by filtration. The reaction mixture waswashed several times with water. The crude product was dissolved inmethanol and set aside to crystallize. Two crops of plate-like crystalswere collected (1.7 g) and thoroughly dried under nitrogen. The finalproduct was homogeneous by TLC (dichloromethane: methanol, 10:1 byvolume, Rf=0.8) and HPLC.

EXAMPLE 2 Synthesis of (+) -2, 2,8-trimethyl-5-(4-chloro-α-hydroxy-benzyl)-pyrido-[4,3-e]-1,3-dioxane

1.1 g (3.5 mmol) of the ketone prepared in Example 1 were poured into a50 ml round bottomed flask and dissolved in 35 ml of dry THF(tetrahydrofuran). The flask was sealed with a septum, placed under anitrogen atmosphere and set into a dry ice/acetone bath.[1S]-N,B-Enantride™ (13.3 ml, 6,65 mmoles) was then added in one portionand the rate of reduction was followed by HPLC (high pressure liquidchromatography) at T - 0, T - 1 hr and T - 2 hr. Typically, most of theketone was reduced to(+)-2,2,8-trimethyl-5(4-chloro-α-hydroxybenzyl)-pyrido-[4,3-e]-1,3-dioxaneafter two hours. The reaction mixture was evaporated to dryness on aroto-vac, the residue was redissolved in dichloromethane, loaded on thetop of a silica gel column (42 g) and eluted with dichloromethane. Theseparation was assayed by TLC and fractions numbers 131-160 werecombined. The solvent was removed by rotary evaporation and the residue(1.05 g) was redissolved in 12 ml of ethyl acetate. On cooling, a fluffywhite crop of crystals precipitated and was collected (0.25 g). Thissample was homogeneous by TLC (dichloromethane:methanol, 10:1 by volume)and HPLC and provided(+)-2,2,8-trimethyl-5-(4-chloro-α-hydroxybenzyl)-pyrido-[4,3-e]-1,3-dioxaneof high enantiomeric enrichment (>86%).

EXAMPLE 3 Deprotection/cyclodehydration of(+)-2,2,8-trimethyl-5-(4-chloro-α-hydroxybenzyl)-pyrido-[4,3-e]-1,3-dioxaneto(+)-3-(4-chlorophenyl)-1,3-dihydro-7-hydroxy-6-methylfuro[3,4-c-pyridine

317 mg (1 mmol) of (+)-2,2,8-trimethyl-5-(4-chloro-α-hydroxybenzyl)-pyrido-[4,3-e]-1,3-dioxane, prepared as described inExample 2, were poured into 100 ml round bottomed flask and dissolved in60 ml of benzene. Two drops of concentrated sulphuric acid were added, aDean-Stark adaptor was attached and the reaction mixture was refluxedfor two hours. The benzene solution (which contained unreacted startingmaterial) was poured off from the yellow green solid which had formed onthe bottom of the flask. The insoluble material was dissolved inmethanol, spotted onto a 2000μ silica gel TLC plate and eluted withdichloromethane: methanol, 7:1 by volume.

The major U.V. visible band which co-eluted with a spot of known(+)-3-(4-chlorophenyl)-1,3-dihydro-7-hydroxy-6-methyl-furo-[3,4-c]-pyridine was excised from the plate and the organicmaterial from the silica was washed with methanol. Removal of themethanol by rotary evaporation gave a solid product shown to be(+)-3-(4-chlorophenyl)-1,3-dihydro-7-hydroxy-6-methylfuro-[3,4-c]-pyridine by spectroscopic andchromatographic comparison with an authentic sample.

Chiral phase HPLC of the isolated product showed it to be a mixture of(-) and (+)-3-(4-chlorophenyl)-1,3-dihydro-7-hydroxy-6-methylfuro-[3,4-c]pyridine in a ratio that is identical to that of the starting(+)-2,2,8-trimethyl-5-(4-chloro-α-hydroxybenzyl)-pyrido-[4,3-e]-1,3-dioxane.

The furo [3,4-c]pyridine derivative compounds obtained according to thisinvention are of use in the various pharmaceutical fields described inU.S. Pat. Nos. 4,383,998, 4,581,363, 4,585,776, 4,569,939, 4,581,362 and4,659,719. Accordingly, this invention also relates to therapeuticcompositions, one active ingredient in which is an enantiomer or amixture of enantiomers wherein one enantiomer is substantiallypredominant.

The appropriate administration modes are described in the abovementioned patents, but the dosage required is lower due to the enhancedactivity of the selected enantiomer or of the enantiomer mixtureswherein said enantiomer is predominant.

PRESENTATION

The preferred administration mode is tablets and capsules. For tablets,each dosage unit contains from 5 to 100 mg or, preferably, 10 to 25 mgof the active principle associated with an appropriate inert carrier,such as starch.

POSOLOGY

In human therapy, the doses to be used are from 50 to 150 mg/day for atleast one week, and preferably for longer periods of time.

What is claimed is:
 1. A method of producing, in non-racemic form (thatis as a single enantiomer or as an enantiomeric mixture in which oneenantiomer predominates), a compound of the formula I: ##STR7## whereinR₁ is selected from the group consisting of a) a straight chainsaturated hydrocarbon groups having from 1 to 5 carbon atoms, b) astraight chain unsaturated hydrocarbon group having from 1 to 5 carbonatoms, c) a heterocyclic group having up to 6 ring atoms, d) acarbomonocyclic group, e) a phenyl group, f) a phenylalkyl group, and g)a phenylalkenyl group, each of said groups a to g being optionallysubstituted with one or more substituents selected from the groupconsisting of halogen atoms, trifluoromethyl groups, alkyl groups havingfrom 1 to 5 carbon atoms, alkoxy groups having from 1 to 5 carbon atoms,alkylthio groups having from 1 to 5 carbon atoms, dialkylamino groups inwhich each alkyl group has from 1 to 5 carbon atoms, dialkylaminoalkoxygroups in which each of the two alkyl groups and the alkoxy group hasfrom 1 to 5 carbon atoms and α- or β-alkoxy-N-pyrrolidinyl groups inwhich the alkoxy group has from 1 to 5 carbon atoms;R₂ is selected froma hydrogen atom and a halogen atom; and R₃ is selected from the groupconsisting of straight chain and branched chain alkyl and alkenyl groupshaving up to 6 carbon atoms, optionally substituted by a substituentselected from the group consisting of hydroxy, cyano, amino groups,substituted amino groups, alkyl groups having up to 4 carbon atoms, andalkenyl groups having up to 4 carbon atoms, comprising: providing asolution of a non-racemic compound of the formula II: ##STR8## whereinR₁, R₂, R₃ are as defined above; and adding concentrated strong acid tosaid solution in an amount sufficient to catalyze adeprotection/cyclodehydration reaction to yield compound I.
 2. Themethod of claim 1 wherein said solution comprises compound II dissolvedin a solvent that from an azeotrope with water.
 3. The method of claim 2wherein said solvent is selected form the group consisting of benzene,toluene, ethyl acetate and chloroform.
 4. The method of claim 1 whereinsaid strong acid is selected from the group consisting of hydrochloricacid, sulfuric acid, perchloric acid and trifluoroacetic acid.
 5. Themethod of claim 1, further comprising purifying compound II by alcoholor ethyl acetate crystallization before forming said solution.
 6. Themethod of claim 1 further comprising the step of recovering saidcompound I from the reaction mixture.
 7. The method of claim 6, whereinsaid recovery step comprises decanting excess solution comprisingunreacted compound II from a residue produced by said cyclodehydrationreaction, dissolving said residue in alcohol to produce a mixture,determining what part of said alcohol mixture is compound I, andisolating compound I from said alcohol mixture.
 8. The method of claim1, wherein the step of providing a solution of non-racemic compound IIcomprises:dissolving the racemic achiral form of compound II in organicsolvent to form a solution; adding an oxidizing agent to said solutiondropwise in an amount sufficient to completely react with all of thecompound II racemate; quenching the excess oxidizing agent with analcohol; cooling the liquid to produce a solid compound precipitate;dissolving said solid crystals in tetrahydrofuran to form a mixture;adding to said mixture a chiral reducing agent to reduce said solidcompound to the desired chiral compound II; and isolating compound IIand dissolving it in a solvent.
 9. The method of claim 8 wherein saidorganic solvent is acetone, said oxidizing agent is Jones Reagent, saidalcohol is isopropanol and said chiral reducing agent is lithium hydride(9-BBN-nopolbenzyl ether adduct).
 10. The method of claim 1, wherein thestep of providing a solution of non-racemic compound IIcomprises:dissolving a compound of the formula III: ##STR9## wherein R₁,R₂ and R₃ are as defined above, in a vigorously stirred fermentingslurry of yeast, water and a carbohydrate; adding additionalcarbohydrate and yeast to provide continued vigorous fermentation toform the desired chiral compound II; continuing said fermentation untilformation of compound II ceases; and isolating compound II anddissolving it in a solvent.